What are the adult indications, initial dose, titration schedule, common adverse effects, contraindications, and special‑population precautions for mirtazapine?

Mirtazapine: Clinical Overview

FDA-Approved Indication

Mirtazapine is FDA-approved for the treatment of major depressive disorder (MDD) in adults. 1, 2 While not FDA-approved for insomnia, it is commonly used off-label for sleep disturbances, particularly when comorbid with depression or anxiety. 1

Initial Dosing

Start mirtazapine at 15 mg once daily at bedtime. 2, 3

• For elderly, debilitated, or frail patients, consider initiating at 7.5 mg at bedtime to minimize sedation risk. 1, 4
• The bedtime dosing schedule capitalizes on the drug's sedating properties and 20-40 hour elimination half-life. 3

Titration Schedule

The effective dosage range is 15-45 mg daily, with 45 mg being the maximum recommended dose. 4, 5

• After starting at 15 mg for 4 days, increase to 30 mg daily for 10 days if tolerated. 6
• If response is insufficient at 30 mg after adequate trial, may increase to maximum of 45 mg daily. 6
• Allow at least 1-2 weeks between dose adjustments due to the long half-life. 5
• Steady-state concentrations are reached after 4 days in adults and 6 days in elderly patients. 7

Onset of Action and Response Assessment

Begin assessing therapeutic response and adverse effects within 1-2 weeks of treatment initiation. 4

• Sleep disturbances and anxiety symptoms may improve within the first week. 3
• Clinical antidepressant effect typically emerges in 2-4 weeks, with full efficacy at 4-6 weeks. 5, 3
• If inadequate response by 6-8 weeks, treatment modification is strongly recommended. 4
• Mirtazapine demonstrates faster onset of action compared to some SSRIs like fluoxetine, paroxetine, and sertraline. 4

Treatment Duration

Continue treatment for 4-9 months after satisfactory response in patients with first-episode MDD. 4

• For patients with 2 or more depressive episodes, longer duration therapy is beneficial. 4
• Long-term studies at 40 weeks show continued improvements in response rates with lower relapse rates. 5

Common Adverse Effects

The most frequently reported adverse effects include:

• Somnolence/sedation (19-23% vs 5-14% placebo) - most common side effect 4, 2, 5
• Increased appetite and weight gain (10-11% vs 1-2% placebo) 4, 2, 5
• Dry mouth (25% vs 16% placebo) 4, 6
• Dizziness 2
• Constipation or diarrhea 4

Notably, mirtazapine lacks the sexual dysfunction, gastrointestinal symptoms, and insomnia commonly seen with SSRIs. 7, 3

Serious Adverse Effects to Monitor

• Agranulocytosis and neutropenia - rare but potentially serious hematological changes requiring monitoring. 6
• Transient elevations in cholesterol levels (mean 3-4% increase) and liver function tests. 5, 6
• Hyponatremia (class effect of antidepressants). 1

Contraindications and Precautions

Exercise caution in patients with:

• Signs or symptoms of depression with compromised respiratory function (asthma, COPD, sleep apnea). 1
• Hepatic or renal insufficiency - requires careful dosage titration and close monitoring. 6
• Cardiac conditions, though mirtazapine has minimal cardiovascular effects compared to tricyclics. 3

Avoid or use with extreme caution:

• During pregnancy or nursing. 1
• In patients under 18 years (safety/effectiveness not established). 1
• With concomitant CNS depressants or alcohol - additive effects on psychomotor performance. 1, 6

Special Population Considerations

Elderly Patients

• Start at lower dose (7.5 mg) and titrate cautiously. 1
• Steady-state reached in 6 days (vs 4 days in younger adults). 7

Hepatic/Renal Impairment

• Requires careful dose titration and regular monitoring for adverse events. 6

Patients with Specific Comorbidities

• Depression with insomnia or sleep disturbances: Mirtazapine is particularly effective due to H1 receptor antagonism. 1, 4, 5
• Depression with anorexia or weight loss: The appetite-stimulating and weight-promoting effects are advantageous. 1, 4
• Depression with anxiety: Effective for comorbid anxiety symptoms, potentially reducing need for additional anxiolytics. 1, 2, 7

Drug Interactions

Mirtazapine has a low propensity for clinically significant drug-drug interactions. 7

• Metabolized primarily by CYP1A2, CYP2D6, and CYP3A4 isoenzymes. 7
• Concomitant use with diazepam or alcohol may impair cognitive/motor performance. 6
• Unlike SSRIs, mirtazapine does not significantly inhibit cytochrome P450 enzymes. 7

Administration Considerations

• Administer on empty stomach to maximize effectiveness. 1
• Once-daily bedtime dosing is standard due to sedating properties and long half-life. 2, 3
• Do not abruptly discontinue - taper over 10-14 days to limit withdrawal symptoms. 1

Safety in Overdose

Mirtazapine appears remarkably safe in overdose. 6, 3

• Cases up to 975 mg caused significant sedation but no cardiovascular/respiratory effects or seizures. 3
• Very low propensity for inducing seizures compared to other antidepressants. 6

Clinical Positioning

Mirtazapine is most effective in moderate to severe depression, not mild depression. 4

• For mild depression, cognitive behavioral therapy is generally preferred over pharmacotherapy. 4
• Particularly suitable when depression is accompanied by insomnia, anxiety, or weight loss. 1, 4
• Represents a potent, well-tolerated alternative with unique mechanism (noradrenergic and specific serotonergic effects). 1, 5